Small molecule inhibition of GPR65 leads to decreased severity of experimental autoimmune encephalomyelitis

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B851
Abstract ID: 4098

Presenting Author:
Jeniffer Hernandez , Associate Professor at Keck Grad. Inst. Sch. of Phrm. and Hlth. Sci.

Abstract:

GPR65 has been shown to be a critical regulator of Th17 cell pathogenicity. Loss of GPR65 in mice results in a decrease in Th17 cells and reduced susceptibility to experimental autoimmune encephalomyelitis (EAE). The CREB/CRTC2 pathway has emerged as an important regulator of immune function. We have previously shown that the CREB/CRTC2 pathway modulates autoimmune disease by promoting differentiation of Th17 cells. In this study we performed RNA-seq to identify Th17 genes regulated by the CREB/CRTC2 pathway. Our RNA-seq analysis led us to uncover the first mechanism of regulation of the orphan receptor GPR65 by the CREB/CRTC2 pathway. We show that GPR65 is a target of the CREB/CRTC2 pathway through expression studies and chromatin immunoprecipitation. In addition, we show that targeting of GPR65 with a small molecule antagonist decreases Th17 cell differentiation and consequently reduces EAE severity. Understanding the regulation of GPR65 will be crucial in developing small molecules to treat patients with Th17 cell-mediated diseases.